Melanoma has a complex, multifactorial etiology that includes genetic predisposition, UV exposure and somatic genetic changes. This project is focused on the discovery of genetic alterations that play a role in the development of melanorna and the use of those genetic biomarkers in the development of two imodels. These two models will 1) provide information about risk factors tbr the probability of having melanoma and 2) risk of metastatic failure in those individuals who do develop melanoma. We will develop the genetic biomarkers for these models by: 1) analyzing the association between germline variants in DNA damage response genes and risk for melanoma; 2) evaluating the mutation spectrum of a panel of receptor tyrosine kinase genes that may play a role malignant transformation and genome instability in melanomas, and 3) identifying patterns of genomic instability in melanoma using a whole genome approach. We hypothesize that by combining established risk factors with novel genetic biomarkers from these three sources, accurate models for both risk of developing disease and risk of metastatic failure in patients who do develop melanoma can be defined for every individual. These risk profiles also will contain important biological information on melanoma initiation and progression that is needed to develop effective prevention, staging and treatment strategies. The specific aims of this project are: Specific Aim 1: To identify low-penetrance melanoma susceptibility alleles in DNA damage response genes, evaluate their interaction with other genetic variants and risk factors in a case-control study and develop a multivariate melanoma etiology model. Specific Aim 2: To analyze a panel of 50 primary melanoma cell lines for mutations in candidate receptor tyrosine kinase genes and validate frequent mutations in 50 patient lesions. Specific Aim 3: To develop a novel molecular profile of melanoma using array-based comparative genomic hybridization (aCGH) to characterize amplifications and deletions across the entire genome at 1 Mb resolution. Specific Aim 4: To validate somatic genetic alterations as risk factors for use in prognostic models that will distinguish melanoma patients at minimal and high risk of metastasis, thus requiring different management strategies.